chr14-95096509-GAGAA-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_177438.3(DICER1):βc.4407_4410delβ(p.Ser1470LeufsTer19) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L1469L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_177438.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.4407_4410del | p.Ser1470LeufsTer19 | frameshift_variant | 23/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.4407_4410del | p.Ser1470LeufsTer19 | frameshift_variant | 23/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461802Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727212
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
DICER1-related tumor predisposition Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota | Nov 10, 2014 | - - |
Pathogenic, criteria provided, single submitter | curation | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jul 01, 2019 | ACMG criteria met: PVS1, PM2, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2023 | This sequence change creates a premature translational stop signal (p.Ser1470Leufs*19) in the DICER1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DICER1 are known to be pathogenic (PMID: 19556464, 21266384). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of DICER1-related disorders. (PMID: 24909177, 25022261, 25118636). ClinVar contains an entry for this variant (Variation ID: 225888). For these reasons, this variant has been classified as Pathogenic. - |
Rhabdomyosarcoma, embryonal, 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Sep 10, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 2021 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified in several patients with personal history consistent with pathogenic variants in this gene (de Kock 2014, Stewart 2014, Abbo 2018, Nakano 2019); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 31408196, 31296931, 30097050, 30178239, 26925222, 25022261, 20822816, 25118636, 29351919) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 03, 2023 | The c.4407_4410delTTCT pathogenic mutation, located in coding exon 22 of the DICER1 gene, results from a deletion of 4 nucleotides between nucleotide positions 4407 and 4410, causing a translational frameshift with a predicted alternate stop codon (p.S1470Lfs*19). This pathogenic mutation has been reported in a child diagnosed with PPB at age 6 months and a pineoblastoma at age 2 years. This child had inherited this mutation from his mother who had a history of multinodular goiter (de Kock L et al. Acta Neuropathol. 2014 Oct; 128(4):583-95). The c.4407_4410delTTCT pathogenic mutation has also been reported in a child diagnosed with PPB at age 4.5 years and nasal chondromesenchymal hamartomas (NCMH) at age 11 years (Stewart DR et al. Hum. Genet. 2014 Nov; 133(11):1443-50). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pineoblastoma Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Jul 15, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at